Primary analysis of a phase II open-label trial of INCB039110, a selective JAK1 inhibitor, in patients with myelofibrosis

Mascarenhas, John; Talpaz, Moshe; Gupta, Vikas; Foltz, Lynda; Savona, Michael R.; Paquette, Ronald; Turner, A. Robert; Coughlin, Paul; Winton, Elliott F.; Burn, Timothy C.; O'Neill, Peter; Clark, Jason Vt; Hunter, Deborah; Assad, Albert; Hoffman, Ronald; Verstovšek, Srđan

doi:10.3324/haematol.2016.151126

Cited by 91 publications

(64 citation statements)

References 22 publications

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“…80 SVRs with this agent were expectedly modest, although they were often associated with some clinical benefit for patients. 79 Approximately one-third of patients achieved the primary end point of $50% reduction in TSS at week 12 in the 2 higher-dose cohorts, and 53.8% of patients requiring RBC transfusions during the preceding 12 weeks achieved a $50% reduction in the number of units transfused during the first 24 weeks on study. 79 Conventional (type 1) adenosine triphosphate-competitive JAK inhibitors bind to and stabilize the active conformation of JAKs, whereas type 2 inhibitors bind to and stabilize the inactive conformation, preventing the kinase from cycling to the active conformation.…”

Section: Other Jak Inhibitors In Development For Mfmentioning

confidence: 99%

“…79 Approximately one-third of patients achieved the primary end point of $50% reduction in TSS at week 12 in the 2 higher-dose cohorts, and 53.8% of patients requiring RBC transfusions during the preceding 12 weeks achieved a $50% reduction in the number of units transfused during the first 24 weeks on study. 79 Conventional (type 1) adenosine triphosphate-competitive JAK inhibitors bind to and stabilize the active conformation of JAKs, whereas type 2 inhibitors bind to and stabilize the inactive conformation, preventing the kinase from cycling to the active conformation. 81 The JAK2 inhibitor persistence is a phenomenon in which JAK-STAT signaling is reactivated despite the presence of a type 1 JAK2 inhibitor via heterodimerization between activated JAK2 and other JAKs, such as JAK1 or TYK2.…”

Section: Other Jak Inhibitors In Development For Mfmentioning

confidence: 99%

“…The JAK1-selective inhibitor INCB039110 has been tested in patients with MF 79 because selectively targeting JAK1 through suppression of cytokines may provide significant symptom benefits to patients with minimal myelosuppression. 80 SVRs with this agent were expectedly modest, although they were often associated with some clinical benefit for patients.…”

Section: Other Jak Inhibitors In Development For Mfmentioning

confidence: 99%

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JAK2 inhibitors for myeloproliferative neoplasms: what is next?

Bose

Verstovšek

2017

Blood

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Since its approval in 2011, the Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib has evolved to become the centerpiece of therapy for myelofibrosis (MF), and its use in patients with hydroxyurea resistant or intolerant polycythemia vera (PV) is steadily increasing. Several other JAK2 inhibitors have entered clinical testing, but none have been approved and many have been discontinued. Importantly, the activity of these agents is not restricted to patients with JAK2 V617F or exon 12 mutations. Although JAK2 inhibitors provide substantial clinical benefit, their disease-modifying activity is limited, and rational combinations with other targeted agents are needed, particularly in MF, in which survival is short. Many such combinations are being explored, as are other novel agents, some of which could successfully be combined with JAK2 inhibitors in the future. In addition, new JAK2 inhibitors with the potential for less myelosuppression continue to be investigated. Given the proven safety and efficacy of ruxolitinib, it is likely that ruxolitinib-based combinations will be a major way forward in drug development for MF. If approved, less myelosuppressive JAK2 inhibitors such as pacritinib or NS-018 could prove to be very useful additions to the therapeutic armamentarium in MF. In PV, inhibitors of histone deacetylases and human double minute 2 have activity, but their role, if any, in the future treatment algorithm is uncertain, given the availability of ruxolitinib and renewed interest in interferons. Ruxolitinib is in late-phase clinical trials in essential thrombocythemia, in which it could fill an important void for patients with troublesome symptoms.

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Section: Other Jak Inhibitors In Development For Mfmentioning

confidence: 99%

Section: Other Jak Inhibitors In Development For Mfmentioning

confidence: 99%

Section: Other Jak Inhibitors In Development For Mfmentioning

confidence: 99%

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JAK2 inhibitors for myeloproliferative neoplasms: what is next?

Bose

Verstovšek

2017

Blood

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“…NS018 is a selective inhibitor of JAK2 and Src that showed a favorable toxicity profile and promising efficacy signals in phase 1; the phase 2 portion of this study is ongoing (30). A phase 2 study of JAK1 inhibitor itacitinib demonstrated the ability of selective JAK1 inhibition to improve splenomegaly and symptoms related to MF while preserving hemoglobin levels (31). A multicenter phase 2 study evaluating itacitibine alone or in combination with low-dose ruxolitinib after ruxolitinib failure is planned (NCT03144687).…”

Section: Jak Inhibitorsmentioning

confidence: 99%

Novel Therapies for Myelofibrosis

Pettit

Odenike

2017

Curr Hematol Malig Rep

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Purpose of Review To provide a contemporary update of novel agents and targets under investigation in myelofibrosis in the JAK inhibitor era. Recent findings Myelofibrosis (MF) is a clonal stem cell disease characterized by marrow fibrosis and a heterogeneous disease phenotype with a variable degree of splenomegaly, cytopenias, and constitutional symptoms that significantly impact quality of life and survival. Overactive JAK/STAT signaling is a hallmark of MF. The only approved therapy for MF, JAK1/2 inhibitor ruxolitinib, can ameliorate splenomegaly, improve symptoms, and prolong survival in some patients. Therapeutic challenges remain, however. Myelosuppression limits the use of ruxolitinib in some patients, eventual drug resistance is common, and the underlying malignant clone persists despite therapy. A deeper understanding of the pathogenesis of MF has informed the development of additional agents. Summary Promising targets under investigation include JAK1 and JAK2, downstream intermediates in related signaling pathways, epigenetic modifiers, pro-inflammatory cytokines, and immune regulators.

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“…(46) Adverse effects included fatigue, constipation, diarrhea, upper respiratory tract infection, cough and nausea. In those without transfusion-requirements, mean hemoglobin values were stable, but overall, new or worsening grade 3 anemia and thrombocytopenia occurred in 33% and 24% of patients.…”

Section: Jak Inhibitorsmentioning

confidence: 99%

Novel therapies for myelofibrosis

Stein

Cervantes

Giles

et al. 2015

Leukemia & Lymphoma

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Myelofibrosis (MF), including primary, post-essential thrombocythemia and post-polycythemia vera MF, associates with a reduced quality of life and shortened life expectancy. Dysregulation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is prominent, even in the absence of the JAK2V617F mutation. Therefore, all symptomatic MF patients may potentially derive benefit from JAK inhibitors. Despite the efficacy of JAK inhibitors in controlling signs and symptoms of MF, they do not eradicate the disease. Therefore, JAK inhibitors are currently being tested in combination with other novel therapies, a strategy which may be more effective in reducing disease burden, either by overcoming JAK inhibitor resistance or targeting additional mechanisms of pathogenesis. Additional targets include modulators of epigenetic regulation, pathways that work downstream from JAK/STAT (i.e., mammalian target of rapamycin/AKT/phosphoinositide 3-kinase,) heat shock protein 90, hedgehog signaling, pro-fibrotic factors, abnormal megakaryocytes and telomerase. In this review, we discuss novel MF therapeutic strategies.

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Primary analysis of a phase II open-label trial of INCB039110, a selective JAK1 inhibitor, in patients with myelofibrosis

Cited by 91 publications

References 22 publications

JAK2 inhibitors for myeloproliferative neoplasms: what is next?

JAK2 inhibitors for myeloproliferative neoplasms: what is next?

Novel Therapies for Myelofibrosis

Novel therapies for myelofibrosis

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